Journal
CURRENT BIOLOGY
Volume 31, Issue 22, Pages 5009-+Publisher
CELL PRESS
DOI: 10.1016/j.cub.2021.09.041
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Funding
- Swiss National Science Foundation [310030-184759]
- Etat de Vaud
- FBM UNIL PhD Fellowship
- Swiss National Science Foundation (SNF) [310030_184759] Funding Source: Swiss National Science Foundation (SNF)
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During NREMS, fluctuation of noradrenaline levels in thalamus are associated with sleep spindle rhythms and heart-rate variations, indicating vigilance-promoting mechanism by LC neurons. Optogenetic activation or inhibition of LC neurons can modulate sleep-spindle clustering and heart-rate variations, affecting sensory arousability during NREMS. Noradrenergic modulation of thalamic circuits plays a key role in maintaining sensory arousability in mammalian NREMS.
To understand what makes sleep vulnerable in disease, it is useful to look at how wake-promoting mechanisms affect healthy sleep. Wake-promoting neuronal activity is inhibited during non-rapid-eye-movement sleep (NREMS). However, sensory vigilance persists in NREMS in animals and humans, suggesting that wake promotion could remain functional. Here, we demonstrate that consolidated mouse NREMS is a brain state with recurrent fluctuations of the wake-promoting neurotransmitter noradrenaline on the -50-s timescale in the thalamus. These fluctuations occurred around mean noradrenaline levels greater than the ones of quiet wakefulness, while noradrenaline (NA) levels declined steeply in REMS. They coincided with a clustering of sleep spindle rhythms in the forebrain and with heart-rate variations, both of which are correlates of sensory arousability. We addressed the origins of these fluctuations by using closed-loop optogenetic locus coeruleus (LC) activation or inhibition timed to moments of low and high spindle activity during NREMS. We could suppress, lock, or entrain sleep-spindle clustering and heart-rate variations, suggesting that both fore- and hindbrain-projecting LC neurons show coordinated infraslow activity variations in natural NREMS. Noradrenergic modulation of thalamic, but not cortical, circuits was required for sleep-spindle clustering and involved NA release into primary sensory and reticular thalamic nuclei that activated both a1- and b-adrenergic receptors to cause slowly decaying membrane depolarizations. Noradrenergic signaling by LC constitutes a vigilance-promoting mechanism that renders mammalian NREMS vulnerable to disruption on the close-to-minute timescale through sustaining thalamocortical and autonomic sensory arousability.
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